Human Mesenchymal Stem Cells Elicit Complement Activation in Human Blood.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4580-4580
Author(s):  
Katarina Le Blanc ◽  
Guido Moll ◽  
Ida Rasmusson ◽  
Kristina Nilsson Ekdahl ◽  
Graciela Elgue ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Human Blood ◽  
Complement System ◽  
Complement Activation ◽  
Immune Modulation ◽  
Effector Cell ◽  
Conflicts Of Interest ◽  
Cell Functions ◽  
The Complement System

Abstract Abstract 4580 Infusion of third-party mesenchymal stem cells (MSCs) appears to be a promising therapy for steroid-refractory acute graft-versus-host disease (GvHD). Little is known about how MSCs interact with the innate immune system after clinical infusion. In this study, we show that exposure of MSCs to ABO-compatible human blood activates the complement system, which triggers complement-mediated effector cell functions, and correlates with the immunosuppressive properties of MSCs. We found deposition of the complement component 3 (C3) derived opsonins iC3b and C3dg on MSCs, and fluid-phase generation of the chemotactic anaphylatoxins C3a and C5a. These events triggered complement receptor 3 (CD11b/CD18)-mediated effector cell activation; but could be prevented by culturing MSCs in human ABserum or by blocking complement function. Our study demonstrates the important role of the complement system as a possible mediator of immune modulation in clinical applications using MSCs, and implies that complement activation may substantially affect the treatment efficiency. Disclosures: No relevant conflicts of interest to declare.

Parathyroid Hormone Stimulates Human Mesenchymal Stem Cells to Enhance the Expansion of Hematopoietic Stem Cells,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3407-3407
Author(s):  
Hisayuki Yao ◽  
Yasuo Miura ◽  
Satoshi Yoshioka ◽  
Yoshihiro Hayashi ◽  
Hideyo Hirai ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Parathyroid Hormone ◽  
Immune Modulation ◽  
Conflicts Of Interest ◽  
Surface Membrane ◽  
Human Mscs ◽  
Free Expansion ◽  
Hematopoietic Stem

Abstract Abstract 3407 Expanding hematopoietic stems cells (HSCs) has a great interest for successful engraftment of donor cells in hematopoietic stem cell transplantation (HSCT). In addition, mesenchymal stem cells (MSCs) show unique features with multi-differentiation, immune-modulation and tissue regeneration capabilities. Recent studies demonstrated the MSC-derived mature osteoblasts play important roles for the maintenance of HSC niche in the bone marrow (BM) microenvironment. We found that culture-expanded human MSCs support the expansion of HSCs and stimulation of MSCs with parathyroid hormone (PTH) further enhances the MSC-mediated expansion of HSCs. Culture-expanded MSCs (2×104 cells/well) were seeded on a 24-well culture plate. Autologous purified CD34+ HSCs (0.6×103 cells/well) was applied on the MSC-grown plate and co-cultured in StemSpan Serum Free Expansion Medium (StemCell Technologies) supplemented with 100ng/mL SCF, 100ng/mL Flt-3 ligand, 50ng/mL TPO and 20ng/mL IL-3. After 10 days of co-culture of HSCs with MSCs, the number of CD34+ cells was increased to 9.0±1.6×103 (Fig. culture condition #2), whereas that cultured in the absence of MSCs was 0.98–8, −1 and □ {7 of the irradiation. The number of leukocytes was decreased to the bottom level around 6–8 days after the irradiation in both PTH-treated and non-treated (control) mice. However, the number of leukocyte showed a steep increase in PTH-treated mice and it reached maximal level on day 14 at 16±5.2×103/mL compared with that of 6.4±1.4×103/mL in the control mice. In vitro experiments confirmed that PTH has no direct effects on the expansion of HSCs. It is suggested that PTH has supportive effects on hematopoietic recover in vivo, probably in part, through acting on MSCs in BM microenvironment. In conclusion, PTH stimulated MSCs to enhance HSC expansion mainly through contribution of surface membrane molecules. A two-step manipulation of MSCs with culture expansion and subsequent PTH stimulation showed enhancement of MSC-mediated expansion of HSCs. This work revealed the novel mechanisms underlying HSC expansion mediated by MSCs. In addition, this novel concept of MSC manipulation could provide HSCT procedure with new technology for effective engraftment of donor hematopoietic cells. Disclosures: No relevant conflicts of interest to declare.

Biological Aspects and Clinical Applications of Mesenchymal Stem Cells: Key Features You Need to be Aware of.

2020 ◽  
Vol 21 ◽  
Author(s):  
Mohammad Saeedi ◽  
Muhammad Sadeqi Nezhad ◽  
Fatemeh Mehranfar ◽  
Mahdieh Golpour ◽  
Mohammad Ali Esakandari ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cancer Cells ◽  
Immune Modulation ◽  
Adult Stem Cells ◽  
Inflammatory Diseases ◽  
High Capacity ◽  
Genetically Engineered ◽  
Cartilage Cells ◽  
Biological Aspects

: Mesenchymal stem cells (MSCs), a form of adult stem cells, are known to have a self-renewing property and the potential to specialize into a multitude of cells and tissues such as adipocytes, cartilage cells, and fibroblasts. MSCs can migrate and home to the desired target zone where inflammation is present. The unique characteristics of MSCs in repairing, differentiation, regeneration, and its high capacity of immune modulation has attracted tremendous attention for exerting them in clinical purposes, as they contribute to tissue regeneration process and anti-tumor activity. The MSCs-based treatment has demonstrated remarkable applicability towards various diseases such as heart and bone malignancies, and cancer cells. Importantly, genetically engineered MSCs, as a state-of-the-art therapeutic approach, could address some clinical hurdles by systemic secretion of cytokines and other agents with a short half-life and high toxicity. Therefore, understanding the biological aspects and the characteristics of MSCs is an imperative issue of concern. Herein, we provide an overview of the therapeutic application and the biological features of MSCs against different inflammatory diseases and cancer cells. We further shed light on MSCs physiological interaction, such as migration, homing, and tissue repairing mechanisms with different healthy and inflamed tissues.

Aberrant activation of complement system in renal grafts is mediated by cold storage

2021 ◽  
Author(s):  
Sorena Lo ◽  
Li Jiang ◽  
Savannah Stacks ◽  
Haixia Lin ◽  
Nirmala Parajuli
Keyword(s):  
Cold Storage ◽  
Complement System ◽  
Complement Activation ◽  
Renal Tubules ◽  
Renal Transplants ◽  
Reducing Conditions ◽  
Tnf Α ◽  
Renal Grafts ◽  
The Impact ◽  
The Complement System

Aberrant complement activation leads to tissue damage during kidney transplantation, and it is recognized as an important target for therapeutic intervention (6, 19, 35, 64). However, it is not clear whether cold storage (CS) triggers the complement pathway in transplanted kidneys. The goal of this study was to determine the impact of CS on complement activation in renal transplants. Male Lewis and Fischer rats were used, and donor rat kidneys were exposed to 4 h or 18 h of CS followed by transplantation (CS+Transplant). To study CS-induced effects, a group with no CS was included in which the kidney was removed and transplanted back to the same rat (autotransplantation, ATx). Complement proteins (C3 and C5b-9) were evaluated with western blotting (reducing and non-reducing conditions) and immunostaining. Western blot of renal extracts or serum indicated that the levels of C3 and C5b-9 increased after CS+Transplant compared to ATx. Quite strikingly, intracellular C3 was profoundly elevated within renal tubules after CS+Transplant but was absent in Sham or ATx groups, which showed only extratubular C3. Similarly, C5b-9 immunofluorescence staining of renal sections showed an increase in C5b-9 deposits in kidneys after CS+Transplant. Real-time PCR (SYBR Green) showed increased expression of CD11b and CD11c, components of complement receptors 3 and 4, respectively, as well as inflammatory markers such as TNF-α. In addition, recombinant TNF-α significantly increased C3 levels in renal cells. Collectively, these results demonstrate that CS activates the complement system in renal transplants.

scholarly journals Effects of Interferon-γ on Proliferation and Ability of Secretion of Human Amniotic Mesenchymal Stem Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5012-5012
Author(s):  
Ya Gao ◽  
Ying Xu ◽  
Weiru Li ◽  
Yintian Zhang ◽  
Baohong Ping ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Conflicts Of Interest ◽  
Interferon Γ ◽  
Cell Counting ◽  
Inflammatory Factors ◽  
Complete Medium ◽  
Amniotic Mesenchymal Stem Cells ◽  
Soluble Hla ◽  
Ifn Γ

Objective:The immunoregulatory properties and proliferation of mesenchymal stem cells (MSCs) could be affected by inflammatory factors. However, there have been few studies about human amniotic MSCs (hAMSCs). We investigated the effects of interferon (IFN)-γ on the proliferation and apoptosis of hAMSCs, and measured the level of inflammatory factors secreted by hAMSCs. Result:hAMSCs were cultured with complete medium with different concentrations of IFN-γ. We detected the proliferation of hAMSCs by Cell Counting Kit-8 assays, analysed apoptosis by flow cytometry (FCM) at 48 h, and mesasured the level of inflammatory factors such as solube HLA-G and prostaglandin E2 (PGE2) in the supernatant at 48 h by ELISA. The level of kynurenine (KYN) was measured by ultraviolet spectrophotometry. As culture time increased, the proliferation of hAMSCs with different concentrations of IFN-γ increased rapidly from day 1 to day 4, and then the growth rate slowed. FCM indicated that there was no significant apoptosis in the 100 ng/ml IFN-γ group compared with cells without IFN-γ. The level of PGE2 and soluble HLA-G in cells with IFN-γ was higher compared with those without IFN-γ. The level of KYN increased significantly in the cells with IFN-γ. Conclusion:IFN-γ did not affect the growth and proliferation of hAMSCs, and promoted secretion of PGE2 and soluble HLA-G, and enhanced activity of indoleamine 2,3-dioxygenase (IDO), providing a theoretical basis for hAMSCs to prevent and treat graft-versus-host disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals Ca(2+) Oscillations and Its Transporters in Mesenchymal Stem Cells

2010 ◽  
pp. 323-329 ◽  
Author(s):  
B Ye
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Replacement Therapy ◽  
Cell Types ◽  
Cell Replacement Therapy ◽  
Cell Replacement ◽  
Cell Functions ◽  
The Past ◽  
Intracellular Ca

Intracellular free Ca(2+) is one of important biological signals regulating a number of cell functions. It has been discussed widely and extensively in several cell types during the past two decades. Attention has been paid to the Ca2+ transportation in mesenchymal stem cells in recent years as mesenchymal stem cells have gained considerable interest due to their potential for cell replacement therapy and tissue engineering. In this paper, roles of intracellular Ca(2+) oscillations and its transporters in mesenchymal stem cells have been reviewed.

scholarly journals Dependence of Spreading and Differentiation of Mesenchymal Stem Cells on Micropatterned Surface Area

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Wei Song ◽  
Naoki Kawazoe ◽  
Guoping Chen
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Single Cell ◽  
Adipogenic Differentiation ◽  
Cell Spreading ◽  
Poly Vinyl Alcohol ◽  
Cell Array ◽  
Cell Functions

Micropatterning technology is a highly advantageous approach for directly assessing and comparing the effects of different factors on stem cell functions. In this study, poly(vinyl alcohol)- (PVA-) micropatterned polystyrene surfaces were prepared using photoreactive PVA and ultraviolet photolithography with a photomask. The micropatterned surface was suitable for single-cell array formation and long-term cell culture due to the nanometer thickness of nonadhesive PVA layer. Different degrees of cell spreading with the same cell shape were established by adjusting the sizes of circular, cell-adhesive polystyrene micropatterns. Cell spreading and differentiation of mesenchymal stem cells (MSCs) on the micropatterns were investigated at the single-cell level. The assembly and organization of the cytoskeleton were regulated by the degree of cell spreading. Individual MSCs on large circular micropatterns exhibited a more highly ordered arrangement of actin filaments than did those on the small circular micropatterns. Furthermore, the differentiation of MSCs was dependent on the degree of cell spreading. Increased cell spreading facilitated the osteogenic differentiation but suppressed the adipogenic differentiation of MSCs. This micropatterning method is valuable for stem cell research in tissue engineering and regenerative medicine.

scholarly journals Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease

2017 ◽  
Vol 114 (15) ◽  
pp. 3987-3992 ◽  
Author(s):  
Tamara L. Lenis ◽  
Shanta Sarfare ◽  
Zhichun Jiang ◽  
Marcia B. Lloyd ◽  
Dean Bok ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Retinal Pigment Epithelium ◽  
Complement System ◽  
Complement Activation ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Host Cells ◽  
Etiologic Factor ◽  
Photoreceptor Degeneration ◽  
The Complement System

Recessive Stargardt macular degeneration (STGD1) is caused by mutations in the gene for the ABCA4 transporter in photoreceptor outer segments. STGD1 patients and Abca4−/− (STGD1) mice exhibit buildup of bisretinoid-containing lipofuscin pigments in the retinal pigment epithelium (RPE), increased oxidative stress, augmented complement activation and slow degeneration of photoreceptors. A reduction in complement negative regulatory proteins (CRPs), possibly owing to bisretinoid accumulation, may be responsible for the increased complement activation seen on the RPE of STGD1 mice. CRPs prevent attack on host cells by the complement system, and complement receptor 1-like protein y (CRRY) is an important CRP in mice. Here we attempted to rescue the phenotype in STGD1 mice by increasing expression of CRRY in the RPE using a gene therapy approach. We injected recombinant adeno-associated virus containing the CRRY coding sequence (AAV-CRRY) into the subretinal space of 4-wk-old Abca4−/− mice. This resulted in sustained, several-fold increased expression of CRRY in the RPE, which significantly reduced the complement factors C3/C3b in the RPE. Unexpectedly, AAV-CRRY–treated STGD1 mice also showed reduced accumulation of bisretinoids compared with sham-injected STGD1 control mice. Furthermore, we observed slower photoreceptor degeneration and increased visual chromophore in 1-y-old AAV-CRRY–treated STGD1 mice. Rescue of the STGD1 phenotype by AAV-CRRY gene therapy suggests that complement attack on the RPE is an important etiologic factor in STGD1. Modulation of the complement system by locally increasing CRP expression using targeted gene therapy represents a potential treatment strategy for STGD1 and other retinopathies associated with complement dysregulation.

scholarly journals Pretreatment with atorvastatin ameliorates cobra venom factor-induced acute lung inflammation in mice

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Jing Guo ◽  
Min Li ◽  
Yi Yang ◽  
Lin Zhang ◽  
Li-wei Zhang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Protein Content ◽  
Complement System ◽  
Complement Activation ◽  
Lung Inflammation ◽  
Acute Lung Inflammation ◽  
Tnf Α ◽  
The Complement System

Abstract Background The complement system plays a critical role as the pathogenic factor in the models of acute lung injury due to various causes. Cobra venom factor (CVF) is a commonly used complement research tool. The CVF can cause acute inflammation in the lung by producing complement activation components. Atorvastatin (ATR) is a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor approved for control of plasma cholesterol levels. This inhibitor can reduce the acute pulmonary inflammatory response. However, the ability of ATR in treating acute lung inflammation caused by complement activation is still unknown. Therefore, we investigated the effect of ATR on lung inflammation in mice induced by activation of the complement alternative pathway in this study. Methods ATR (10 mg/kg/day via oral gavage) was administered for 7 days before tail vein injection of CVF (25 μg/kg). On the seventh day, all mice were sacrificed 1 h after injection. The lung lobe, bronchoalveolar lavage fluid (BALF), and blood samples were collected. The myeloperoxidase (MPO) activity of the lung homogenate, the leukocyte cell count, and the protein content of BALF were measured. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), P-selectin, and Intercellular cell adhesion molecule-1 (ICAM-1) in BALF and serum were determined by enzyme-linked immunosorbent assay. The pathological change of the lung tissue was observed by hematoxylin and eosin staining. The deposition of C5b-9 in the lung tissue was detected by immunohistochemistry. The phosphorylation of NF-κB p65 in the lung tissues was examined by immunohistochemistry and western blotting. Results The lung inflammation levels were determined by measuring the leukocyte cell numbers and protein content of BALF, the lung MPO activity, and expression and staining of the inflammatory mediators (IL-6 and TNF-α), and adhesion molecules (P-selectin and ICAM-1) for lung lesion. A significant reduction in the lung inflammation levels was observed after 7 days in ATR pre-treated mice with a CVF-induced lung disease. Deposition of C5b-9 was significantly alleviated by ATR pretreatment. Early intervention with ATR significantly reduced the development of acute lung inflammation on the basis of phosphorylation of NF-κB p65 in the lung. Conclusion These findings suggest the identification of ATR treatment for the lung inflammation induced by activating the complement system on the basis of its anti-inflammatory response. Together with the model replicating the complement activating characteristics of acute lung injury, the results may be translatable to the overactivated complement relevant diseases.

scholarly journals Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
Lisa E. Gralinski ◽  
Timothy P. Sheahan ◽  
Thomas E. Morrison ◽  
Vineet D. Menachery ◽  
Kara Jensen ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Host Defense ◽  
Complement System ◽  
Complement Activation ◽  
Fungal Infections ◽  
Central Component ◽  
Lung Pathology ◽  
Inflammatory Monocytes ◽  
The Complement System

ABSTRACT Acute respiratory distress syndrome (ARDS) is immune-driven pathologies that are observed in severe cases of severe acute respiratory syndrome coronavirus (SARS-CoV) infection. SARS-CoV emerged in 2002 to 2003 and led to a global outbreak of SARS. As with the outcome of human infection, intranasal infection of C57BL/6J mice with mouse-adapted SARS-CoV results in high-titer virus replication within the lung, induction of inflammatory cytokines and chemokines, and immune cell infiltration within the lung. Using this model, we investigated the role of the complement system during SARS-CoV infection. We observed activation of the complement cascade in the lung as early as day 1 following SARS-CoV infection. To test whether this activation contributed to protective or pathologic outcomes, we utilized mice deficient in C3 (C3–/–), the central component of the complement system. Relative to C57BL/6J control mice, SARS-CoV-infected C3–/– mice exhibited significantly less weight loss and less respiratory dysfunction despite equivalent viral loads in the lung. Significantly fewer neutrophils and inflammatory monocytes were present in the lungs of C3–/– mice than in C56BL/6J controls, and subsequent studies revealed reduced lung pathology and lower cytokine and chemokine levels in both the lungs and the sera of C3–/– mice than in controls. These studies identify the complement system as an important host mediator of SARS-CoV-induced disease and suggest that complement activation regulates a systemic proinflammatory response to SARS-CoV infection. Furthermore, these data suggest that SARS-CoV-mediated disease is largely immune driven and that inhibiting complement signaling after SARS-CoV infection might function as an effective immune therapeutic. IMPORTANCE The complement system is a critical part of host defense to many bacterial, viral, and fungal infections. It works alongside pattern recognition receptors to stimulate host defense systems in advance of activation of the adaptive immune response. In this study, we directly test the role of complement in SARS-CoV pathogenesis using a mouse model and show that respiratory disease is significantly reduced in the absence of complement even though viral load is unchanged. Complement-deficient mice have reduced neutrophilia in their lungs and reduced systemic inflammation, consistent with the observation that SARS-CoV pathogenesis is an immune-driven disease. These data suggest that inhibition of complement signaling might be an effective treatment option following coronavirus infection.

Human mesenchymal stem cells modulate B-cell functions

Blood ◽  
2006 ◽  
Vol 107 (1) ◽  
pp. 367-372 ◽  
Author(s):  
Anna Corcione ◽  
Federica Benvenuto ◽  
Elisa Ferretti ◽  
Debora Giunti ◽  
Valentina Cappiello ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Function ◽  
Costimulatory Molecule ◽  
Human Mesenchymal Stem Cells ◽  
B Cell Differentiation ◽  
Major Mechanism ◽  
Cell Functions

Abstract Human mesenchymal stem cells (hMSCs) suppress T-cell and dendritic-cell function and represent a promising strategy for cell therapy of autoimmune diseases. Nevertheless, no information is currently available on the effects of hMSCs on B cells, which may have a large impact on the clinical use of these cells. hMSCs isolated from the bone marrow and B cells purified from the peripheral blood of healthy donors were cocultured with different B-cell tropic stimuli. B-cell proliferation was inhibited by hMSCs through an arrest in the G0/G1 phase of the cell cycle and not through the induction of apoptosis. A major mechanism of B-cell suppression was hMSC production of soluble factors, as indicated by transwell experiments. hMSCs inhibited B-cell differentiation because IgM, IgG, and IgA production was significantly impaired. CXCR4, CXCR5, and CCR7 B-cell expression, as well as chemotaxis to CXCL12, the CXCR4 ligand, and CXCL13, the CXCR5 ligand, were significantly down-regulated by hMSCs, suggesting that these cells affect chemotactic properties of B cells. B-cell costimulatory molecule expression and cytokine production were unaffected by hMSCs. These results further support the potential therapeutic use of hMSCs in immune-mediated disorders, including those in which B cells play a major role.

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